Osteoarthritis (OA) is the most common musculoskeletal disease among the aging population in the United States and throughout the world. OA is characterized by degeneration of articular cartilage of the joints in hands, knees, spine and hips. While conditions predisposing to the development of OA have been identified the actual causes remain unknown. The current treatment options are limited to relief of symptoms using nonsteroidal anti-inflammatory drugs (NSAIDs). Due to complications associated with NSAIDs therapy, the use of herbal extracts for the treatment of OA is on the rise but most of these agents, sold as dietary supplements, have not been evaluated for their efficacy and safety. Pomegranate fruit (Punica granatum L) is revered through the ages for its medicinal properties. Pomegranate fruit or its extract (PFE) is widely used in several traditional medicinal systems for the treatment of inflammation and pain in arthritis and other diseases. Edible part of pomegranate fruit (PF) is rich in anthocyanins, a group of polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Published work from this laboratory has shown that PFE exert a potent inhibitory effect on IL-IB-induced activation of p38-MAPK and JNK, NF-kB and expression of matrix metalloproteinases (MMPs) by human cartilage explants and chondrocytes in vitro. However, the mechanism of the inhibition of catabolic response remains elusive. Based on our published and preliminary studies we hypothesize that "pomegranate fruit extract (PFE) inhibit the cartilage degrading effects of IL-1 (3 by regulating the activation of signal transduction pathways and transcription factors which negatively or positively affect the IL1-(3 -induced transcription of genes associated with the catabolic or anabolic response in human chondrocytes". Proposed studies will determine whether PFE inhibit the MKK3 and MKK6 kinases (Specific Aim 1);inhibit the IL-1p-induced activation of NF-KB by modulating the activation of kinases upstream of kB (inhibitor of NF-KB) including IKKa and IKK(3 (Specific Aim 2);whether PFE inhibit the IL-1(3-induced oxidative stress and dedifferentiation of human chondrocytes (Specific Aims 3, 4);and determine whether "consumption of PFE will inhibit the cartilage degradation and suppress the progression of experimentally induced OA in rabbits (Specific Aim 5). Our findings may open new avenues regarding the use of PFE or compounds derived from it for the treatment and/or prevention of OA.